There is a clear relationship between weight gain, obesity and a number of common pathological and metabolic disorders, including diabetes, insulin resistance, metabolic syndrome, cardiovascular disease, hypertension, atherosclerosis, and elevated blood lipid levels. Due to the increasing prevalence of overweight and obesity in the global population, body weight management has become a key element of modern healthcare, and more effective means of weight reduction are urgently needed.
Overweight and obesity result from a level of energy intake which exceeds the body's energy expenditure. Reduction of body weight may be achieved via reducing total caloric intake from the diet, or by reducing caloric intake contributed by specific dietary components. For example, caloric intake can be reduced via control of dietary fat consumption or via control of fat absorption in vivo. Because of its role in the pathogenesis of cardiovascular disease, control of fat intake is particularly important.
Lifestyle changes are very difficult to implement, and as physical activity in the developed world continues to decline and Western-style diets are adopted by developing countries, the prevalence of obesity and its associated health problems is expected to increase world-wide. However, the effectiveness of currently-available drugs and supplements for promoting weight control or weight loss is very variable, particularly if they are not used in conjunction with a calorie-restricted diet plus an exercise regimen.
Currently there are two US Food and Drug Administration-approved anti-obesity drugs, Orlistat and Sibutramine. Orlistat, marketed under the names Xenical and Alli, inhibits pancreatic lipase activity in the small intestine. Pancreatic lipase breaks down triglycerides into fatty acids and monoglycerides, which are subsequently absorbed into the body. Thus inhibition of lipase activity effectively reduces fat absorption. A reduced fat diet is recommended while taking this medication. In the absence of major dietary changes, the adverse effects of gastrointestinal discomfort, diarrhea and flatulence have limited its use. (See Heck et al.: Orlistat, a new lipase inhibitor for the management of obesity, Pharmacotherapy 20:270-279. 2000). There have also been 32 reports of severe liver damage, including 6 cases of liver failure, in patients taking this agent between 1999 and 2008 (US Food and Drug Administration press release 24 Aug. 2009). Sibutramine, marketed under the names Meridia and Reductil, is a serotonin and norepinephrine reuptake inhibitor, and reduces body weight by suppressing appetite. It has significant side effects, such as hypertension, and life-style modifications, such as a reduced fat diet, are also recommended for patients taking this agent.
Because of the side-effect profiles and limited efficacy of these approved agents, additional effective agents with no or minimum side-effects are urgently needed in the art.
Chitosan, which is obtained from the shells of crustaceans, may “trap” or absorb large quantities of fat and thereby inhibits intestinal fat absorption. Its activity is at least to some extent dependent on pH and lipid type.
The anti-hyperlipidaemic effects of a number of plant fibre-containing materials, such as pectin, corn fibre, beta-glucan, guar gum, gum acacia, psyllium, glucomannan, and the like, have long been known. The main fat-binding constituent of these plant materials, regardless of the specific plant origin, is an ionic polysaccharide called pectin. Pectin is a natural part of the human diet, being found in plant cell walls, but does not contribute significantly to nutrition. Pectin is widely found in plants such as citrus, apple, and cactus.
However, there is a lack of scientific evidence for the efficacy of fibre materials such as corn fibre, guar gum and gum acacia as anti-hyperlipidaemic agents. Moreover, the anti-hyperlipidaemic effect is often compromised by the high doses which are necessary with certain plant fibres; for example, psyllium is given at a dose of up to 10.2 g/day. Without sufficient water intake, these high doses of fibre often increase the risk of bowel obstruction. Safety issues also arise for plant fibre products such as glucomannan, which can cause choking due to its high swelling index, and beta-glucan, which can provoke allergic attacks in individuals with gluten allergy. Additionally, the consumption of large amounts of dietary fibre often has unwanted side-effects such as flatulence, and a diet comprising more than 60 g fibre per day may result in deficiencies of minerals such as calcium, iron, or zinc.
Various species of cactus, which are commonly widely found in Mexico, some South American countries, and other arid and semi-arid parts of the world, are widely grown as food crops. The most important of these domesticated species of cactus is Opuntia ficus-indica, whose fruits (tunas) and leaves (nopalitos) are consumed, and this cactus has also been proposed as an industrial source of pectin.
The pectin in Opuntia ficus-indica is reported to be effective in lowering serum cholesterol by a mechanism similar to that of bile acid binding, resulting in an increase in fecal bile acid excretion, which may then increase hepatic synthesis of bile acids and liver depletion of cholesterol, resulting in a higher rate of endogenous cholesterol synthesis and reduced serum cholesterol concentrations (Fernandez et al: J. Nutr. 1990 120 1283-1290; J. Nutr. 1992 122 2330-2340; J. Nutr. 1994 124 817-824). However, these experimental approaches yielded inconsistent results, which have not been independently confirmed. Hence the mechanisms underlying the effects of pectin have not yet been clearly elucidated.
Powdered preparations of various plant parts of Opuntia ficus-indica are commercially available. In most cases these use dried and powdered plant parts, which have not been subjected to any other processing.
European Patent No. 1377183 discloses a preparation having the property of fixing fats, derived from natural cactus cladodes of Opuntia ficus-indica. This preparation is in the form of a powder comprising particles at least 70% of which by weight are smaller than 100 μm, and is produced without chemical conversion or addition, thus maintaining the native fat-binding ability of the fibres. This specification emphasizes the fat-fixing or binding capability of the cactus fibre, based on a specific ratio between fat and fibre.
Other plants, such as Camellia sinensis, Ascophyllum nodosum, Tellima grandiflora, Garcinia cambogia, and Salacia reticulata have been historically used as anti-hyperlipidaemic agents, either as single active ingredients or in combination. In particular, extracts of Salacia reticulata are widely used in Ayurvedic medicine and in Japan for the prevention and treatment of hyperglycaemia, diabetes and other conditions. Various components of this extract have hypoglycaemic effects, inhibit the activity of a number of enzymes involved in carbohydrate metabolism, and increase insulin sensitivity. The aqueous extract from the stem and root of Salacia reticulata has potent alpha-glucosidase and alpha-amylase inhibitory activity.
It is reported that cyclodextrins, especially alpha-cyclodextrin, may have a beneficial effect on blood lipid levels or preventing body weight gain. However, a very high daily dosage is needed to show any significant effect.
Among the methods proposed in the art for maintaining healthy blood cholesterol levels and control of body weight is the control of fat absorption from the diet. Many options for achieving this control have been proposed, but the degree of success varies. The prior art methods have the problems of requiring a high dosage to bring about any observed effect, and adverse side-effects such as flatulence, diarrhea, abdominal cramps and bloating associated with the consumption of a high fibre diet. These factors limit the acceptability of the prior art products to consumers because of the unpleasantness of the side-effects and the relatively high cost of treatment or maintenance. Therefore there is a continued need for new compositions and methods for maintaining healthy blood cholesterol levels and control of body weight and/or obesity.